The proposed research is based on the applicant's observation that the histidine analogue L-histidinol ellicits different growth responses from normal and tumorigenic cells. Normal cells are maintained in Go and hence protected from S-phase drugs by histidinol. Transformed cells continue cell cycle transit and are killed by S-phase drugs in the presence of histidinol. These differential responses are observed in a wide variety of mouse cell lines, can be extended to cells of human origin, persist under cocultivation conditions and are assumed to reflect the loss of normal growth responses to suboptimal nutritional conditions which attends transformation. Thus, L-histidinol (1) provides a probe for studying proliferative control mechanisms, (2) allows a procedure for isolating specific variants of transformed cells; and (3) suggests a means of conferring an operational-specificity upon anticancer drugs. Accordingly, I propose: (1) To investigate the mechanistic basis of the differential growth responses of normal and transformed cells to histidinol by comparing its uptake and effects on macromolecular synthesis, low molecular weight nutrient assimilation and proliferative responses in the two cell types; (2) To isolate and characterize histidinol-responsive mutants of transformed cells which will be generated by chemical mutangenesis and selected by histidinol-dependent resistance to S-phase drugs. Variants which enter Go in the presence of the analogue (i.e. histidinol-responsive) will be assayed by conventional transformation parameters to clarify relationships between aberrant growth responses and oncogenicity; and (3) To attempt to confer specificity upon cancer drugs in vivo, using histidinol to mediate differential proliferative responses from normal and neoplastic cells in mice. This will involve an analysis of the effects of histidinol on myelopoeitic stem cells and tumor cells in vivo and an analysis of the efficacy of the "histidinol/anticancer drug" approach in mice bearing various tumors at various burdens.